Synthesis of the octahydronaphthalene core of nahuoic acid A via a B(C6F5)3-catalyzed intramolecular Diels–Alder (IMDA) reaction

Abstract

Model tetraenal 9b underwent intramolecular Diels–Alder cycloaddition in CH₂Cl₂ at −10 °C under catalysis by the bulky Lewis acid B(C₆F₅)₃ to deliver as major components the cis-fused angularly-methylated octahydronaphthalene products, which are formed through the alternative exo orientations of the reacting moieties. One of these diastereomers features the relative and absolute configuration present in the core of nahuoic acid A, a natural product that acts as a cofactor-competitive inhibitor of the lysine methyl transferase SETD8. By contrast, catalysis of the reaction by Me₂AlCl at −40 °C selectively afforded the trans-fused isomer resulting from the Re-endo orientation.